ABSTRACT ? CLINICAL PROJECT In this OPTI-MOM U54 OPRC application, we seek to optimize drug treatment across the changing physiologic milieu of pregnancy. Our goal is to maximally reduce the burden of major depressive disorder (MDD) while minimizing adverse effects in pregnant women who have decided to continue SSRI pharmacotherapy. The Clinical Research Project is the foundation of the work described in the OPRC application because the longitudinal evaluations of pregnant women provide novel data collection opportunities for both the Basic/Translational and Pilot studies. Two hundred pregnant women who have elected to continue one of the three most commonly prescribed SSRIs (sertraline, fluoxetine or citalopram/escitalopram) for treatment of MDD throughout pregnancy and postpartum will be recruited into this study. The progressive changes in trough plasma drug and metabolite concentrations will be determined at monthly intervals during pregnancy and twice post-birth. We anticipate that plasma parent drug SSRI concentrations will decline and metabolite-to-parent drug ratios will increase across pregnancy. We will obtain serial evaluations of depressive and anxiety symptoms, maternal function and medication side effects to evaluate their association with plasma SSRI drug and metabolite concentrations. Metabolic probe studies will be conducted to evaluate the activity of the cytochrome P450 (CYP) enzymes involved in the metabolism of the three SSRIs (CYP2D6, 3A4, 2C19 and 2C9) at two time points. These studies will be conducted during the third trimester pregnancy (32 + 2 weeks), when maximal changes in their activity occur and at 14 + 2 weeks postpartum, which will approximate the non-pregnant baseline activity of these enzymes. Consistent with prior studies, we anticipate that the activities of CYP2D6 and 3A4 will increase and 2C19 will decrease during pregnancy. We will compare maternal CSF SSRI and metabolite concentrations (obtained in women receiving spinal-epidural analgesia for labor/delivery) with psychiatric symptom levels and adverse event occurrence. The data collected in the Clinical Research Project (drug and metabolite concentrations, psychiatric symptom levels, adverse event occurrences) will be used in the Basic/Translational and Pilot Studies. The integrated results of our combined clinical, basic/translational and pilot studies will provide the evidence to support the development of therapeutic guidelines for the treatment of MDD in women throughout pregnancy.